Principal Investigator/Program Director (Last, First, Middle): Evans, Christopher J., Ph.D., Component III Component III: Endogenous Opioid Systems Mediating Reward, Choice and Habit. ABSTRACT: Endogenous opioid systems are considered important mediators of natural reward, as significant factors mediating acute and chronic responses to multiple abused drugs, and as potential regulators of affective state. However, whether endogenous opioids are solely "hedonic mediators" or are also involved directly in the reinforcement of responses to rewarding stimuli is unclear. The compulsive or habitual nature of drug- taking behavior is increasingly recognized as a major factor in addiction, and endogenous opioids may be key components of habit-forming circuitry. We will employ a battery of operant tasks in rats and in MOR-, DOR-, enkephalin- and B-endorphin-deficient mice designed to dissect the role of these components of opioid systems within specific basal forebrain regions, including the nucleus accumbens, ventral pallidum and amygdaloid nuclei, in mediating goal-directed versus habitual aspects of responses to natural rewards such as sucrose. Subsequently, we will identify the role of these specific opioid systems in the transition from flexible, goal-directed, reward seeking behavior to automatic habit-driven responding induced by repeated opiate exposure. Microdialysis will be used to provide evidence of opioid peptide release in such identified brain regions during performance of these tasks and on the influence of such release on dopamine release in dorsolateral striatum as a function of the transfer from flexible goal-directed reward seeking behavior to habitual responding. Since intact neurokinin and cannabinoid systems are reportedly required for opiate conditioned place preference and self-administration we will apply the same behavioral battery to Tac-1- and CB-1 KO mice to determine whether deficits lie in goal-directed or habitual aspects of responses to natural rewards in these models. In vivo phospho-MAP kinase responses to opiates will be compared to identify anatomical loci wherein opiate function is compromised. These studies will increase our understanding of factors underlying the transition from the controlled, deliberated pursuit of rewarding events, such as drugs of abuse, to compulsive drug-seeking, a key issue for the development of effective medications to treat addiction to multiple classes of abused substances. Primary